BB30044: Glutamate (RW)
GLUTAMATE
Mediates the majority of fast excitatory neurotransmission in the
nervous system
~ 60-90% of synapses are glutamatergic (they synthesise, produce
and package glutamate)
-- However, it is difficult to assign a synapse as ‘glutamatergic’ using
markers as glutamate is also involved in metabolism, so is found in
all cells
Concentration of glutamate in grey matter is 10-15 umol/g
~80% of energy expenditure in brain is used in the regulation of
glutamatergic activity
Potentially neurotoxic if glutamate homeostasis is lost
Neurophysiological functions
Mediator of: sensory information, motor coordination, emotions,
cognition, memory formation/retrieval, development &
synaptogenesis.
Involved pathophysiologically in: excitotoxic neuronal damage,
seizure activity & pain
Central metabolic role in the brain
The major pathway producing stored
glutamate is the conversion of glutamine
to glutamate by the enzyme
glutaminase. This loads vesicles with
glutamate to mediate excitatory
transmission.
Glutamate is also the precursor for GABA
(converted by the enzyme GAD), the principle inhibitory
neurotransmitter in the nervous system.
Vesicular packaging:
Mitochondrial-associated enzyme activity (glutaminase) converts
glutamine to glutamate. This is then packaged into synaptic vesicles
by VGLUTs (vesicular glutamate transporters) at a high
concentration, to be released into the synapse via exocytosis.
Brain distribution of VGLUTs:
VGLUTs are vesicular transporters involved in glutamate packing
into vesicles.
3 flavours, which show anatomically distinct distributions throughout
the brain: VGLUT1 is located
principally in the cortex &
, hippocampus, VLUT2 in the thalamus and VGLUT3 is distributed
through other brain regions.
VGLUT1 and 2 are therefore useful markers of glutamatergic
synapses
Glutamate transporters:
There are also cell-surface transporters of glutamate: EEATs
(excitatory amino acid transporters).
These are Na2+-dependent high affinity plasma membrane
transporters. Involved in the reuptake of glutamate into nerve
terminals, transport into post-synaptic neurons and clearance into
glial cells
5 types in the nervous system (EEAT1-5): EEAT1 and EEAT2 mainly
glial expression
Important in relation to aberrant glutamate transmission in disease,
and important drug targets.
Glutamatergic synapse:
Glutamate can act on 3 post-synaptic receptor types, which drives
post-synaptic signalling.
EEAT2 is the principle glutamate transporter on glial cells – rapidly
removes glutamate from the synapse, preventing it from reaching
excitotoxic synaptic
levels. Glutamate is
then converted back
into glutamine for
export out o the
astrocyte back into the
pre-synaptic neuron,
to resynthesise
glutamate. This is
called the glutamate-
glutamine shuttle, and
it requires much ATP
to maintain transport
activity.
SN protein is the glial transporter for exported glutamine, SA
transports glutamine back into the neuron. This conversion to
glutamine is necessary because recycling glutamate itself would risk
it reaching excitotoxic levels, leading to neuronal damage.
Glutamate receptor subtypes:
Two principle subtypes:
ionotropic (ligand-gated ion
GLUTAMATE
Mediates the majority of fast excitatory neurotransmission in the
nervous system
~ 60-90% of synapses are glutamatergic (they synthesise, produce
and package glutamate)
-- However, it is difficult to assign a synapse as ‘glutamatergic’ using
markers as glutamate is also involved in metabolism, so is found in
all cells
Concentration of glutamate in grey matter is 10-15 umol/g
~80% of energy expenditure in brain is used in the regulation of
glutamatergic activity
Potentially neurotoxic if glutamate homeostasis is lost
Neurophysiological functions
Mediator of: sensory information, motor coordination, emotions,
cognition, memory formation/retrieval, development &
synaptogenesis.
Involved pathophysiologically in: excitotoxic neuronal damage,
seizure activity & pain
Central metabolic role in the brain
The major pathway producing stored
glutamate is the conversion of glutamine
to glutamate by the enzyme
glutaminase. This loads vesicles with
glutamate to mediate excitatory
transmission.
Glutamate is also the precursor for GABA
(converted by the enzyme GAD), the principle inhibitory
neurotransmitter in the nervous system.
Vesicular packaging:
Mitochondrial-associated enzyme activity (glutaminase) converts
glutamine to glutamate. This is then packaged into synaptic vesicles
by VGLUTs (vesicular glutamate transporters) at a high
concentration, to be released into the synapse via exocytosis.
Brain distribution of VGLUTs:
VGLUTs are vesicular transporters involved in glutamate packing
into vesicles.
3 flavours, which show anatomically distinct distributions throughout
the brain: VGLUT1 is located
principally in the cortex &
, hippocampus, VLUT2 in the thalamus and VGLUT3 is distributed
through other brain regions.
VGLUT1 and 2 are therefore useful markers of glutamatergic
synapses
Glutamate transporters:
There are also cell-surface transporters of glutamate: EEATs
(excitatory amino acid transporters).
These are Na2+-dependent high affinity plasma membrane
transporters. Involved in the reuptake of glutamate into nerve
terminals, transport into post-synaptic neurons and clearance into
glial cells
5 types in the nervous system (EEAT1-5): EEAT1 and EEAT2 mainly
glial expression
Important in relation to aberrant glutamate transmission in disease,
and important drug targets.
Glutamatergic synapse:
Glutamate can act on 3 post-synaptic receptor types, which drives
post-synaptic signalling.
EEAT2 is the principle glutamate transporter on glial cells – rapidly
removes glutamate from the synapse, preventing it from reaching
excitotoxic synaptic
levels. Glutamate is
then converted back
into glutamine for
export out o the
astrocyte back into the
pre-synaptic neuron,
to resynthesise
glutamate. This is
called the glutamate-
glutamine shuttle, and
it requires much ATP
to maintain transport
activity.
SN protein is the glial transporter for exported glutamine, SA
transports glutamine back into the neuron. This conversion to
glutamine is necessary because recycling glutamate itself would risk
it reaching excitotoxic levels, leading to neuronal damage.
Glutamate receptor subtypes:
Two principle subtypes:
ionotropic (ligand-gated ion
